Birth defects in infants of diabetic mothers: A historical review

Background: Over the past 80+ years, outcomes in diabetic pregnancies have improved remarkably. In the preinsulin era, both fetal and maternal deaths were common. After insulin was discovered, the likelihood of a successful pregnancy increased, but fetal losses were still common. By the end of the 20th century, a number of medical advances allowed women with diabetes to reasonably expect to deliver a healthy infant, although the perinatal mortality rate was twice that reported for women without diabetes. The excess losses were attributable to birth defects.

Objective: The purpose of this article was to use the recognition of, and approach to, birth defects in infants of mothers with diabetes as an example of the gradual evolution of clinical care and research from the dawn of the insulin era to the age of molecular biology.

Methods: Archival material from the Joslin Diabetes Center (Boston, Massachusetts) was used to document the early history of the problem. Particular emphasis was given to the writings of Priscilla White, MD. Illustrative articles, especially those cited in textbooks, were chosen to highlight developments over the mid to late 20th century.

Results: Before the discovery of insulin, maternal death was the primary issue in diabetic pregnancies. With the availability of insulin, the maternal death rate decreased sharply and fetal deaths became the preeminent problem. Many of these losses were due to iatrogenic prematurity complicated by respiratory distress syndrome; early deliveries avoided stillbirth in late gestation. In the last quarter of the 20th century, methods of assessing fetal well-being and lung maturity allowed pregnancies to proceed nearer to term. Birth defects then emerged as the leading cause of perinatal mortality. The risk for birth defects was linked to diabetes control early in the first trimester, and the mechanism was related to free oxygen radicals from excess glucose. Preconception programs have been shown to reduce the risk.

Conclusions: Clinical advances often are not dramatic. This article illustrates how resolution of a problem may evolve incrementally over decades. Birth defects, once unnoticed in infants of diabetic mothers, became a leading concern. It is now possible to reduce the incidence of these defects to levels seen in nondiabetic pregnancies. Epigenetic mechanisms responsible for malformations have been elucidated.